HIV and AIDs I Flashcards by Joel Glotfelty

Characterized by immunodeficiency resulting from loss of CD4+ T lymphocytes, and development of lifethreatening opportunistic infections

AIDs

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One of the most prevalent places of HIV infection in the world is

Africa south of the sahara

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In infected persons, infectious quantities of HIV (and infected cells, also infectious) are present in blood, CSF, and semen, with smaller quantities in

Vaginal secretions and milk

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Spread by parenteral exposure to blood, sexual intercourse, perinatally, and rarely from other forms of contact

HIV

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Before testing was available, many people were infected with HIV via

Transfusions

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Increase the risk of transmission, by damaging mucosal barriers and locally increasing the number of white blood cells which may become infected

Genital tract infections or injuries

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Present in human seminal plasma was found to increase infectivity of virions by many orders of magnitude, making this interaction an attractive potential target for drug development

Prostatic acid phosphatase fragment

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The decline in deths from AIDs after 1995 reflects the development of a

Highly-Active Anti-Retroviral Therapy (HAART)

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The use of a combination of two RT inhibitors plus a protease inhibitor

HAART

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The biology of HIV is deeply intertwined with the biology of its

Host cells

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HIV gene products replicate its genome and form the structural components of

New Virions

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A recent survey identified over 250 host-cell proteins required for efficient

HIV replication

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Cytosolic contents are wrapped in a double shell of membrane and delivered to endosomes in

Autophagy

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Normally function in formation of multi-vesicular bodies and degradation of plasma membrane proteins, are required for budding of HIV virions

Proteins of the ESCRT complexes (Endosomal Sorting Complexes Required for Transport)

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The primary receptor for HIV is

CD4

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The cell tropism of HIV is largely determined by the distribution of

CD4

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A plasma membrane glycoprotein that in structure resembles an immunoglobulin heavy chain, with four immunoglobulin-type domains

CD4

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CD4 is present on helper T cells and cells of the monocyte/macrophage lineage, including dendritic cells of epithelia, which may be the initial cells infected with

Sexually transmitted HIV

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HIV binding to dendritic cells may also facilitate infection of

T cells

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A surface protein of dendritic cells that binds HIV virions to the cell surface

DC-SIGN

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Attract T cells, which then become infected

Dendritic cell chemokines

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After infection macrophages can spread HIV, especially to secondary lymphoid organs and the

Brain

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Can block HIV infection by occupying the receptor

Chemokine receptors

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About 1% of U.S. Caucasians (and a lower faction of Black and Hispanic Americans) are homozygous for a deletion in the gene for the receptor

CCR5

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Such persons have slower progression of disease after infection. However, they eventually develop

AIDS

The number of CCR5 gene copies varies between individuals - the higher the copy number the more rapid the progression to

AIDs

Some CD4- cells can be infected with HIV in vivo, especially brain astrocytes and oligodendrocytes and epithelial cells of the

Bowel

Here, the receptor may be a

Glycolipid, galactosyl ceramide

The ability of HIV to establish productive infection depends on the state of the cell infected. Monocytes and resting T cells produce little if any

Virus

However, these support abundant virus replication

Macrophages and activated T cells

The state of the infected cell may affect reverse transcription, integration, or

Virus transcription

The HIV promoter binds numerous cellular transcription factors (notably NF-KB) which are activated when T cells are stimulated by cytokines such as

TNF

Thus, T cells can not be stimulted to fight HIV without also stimulating its

Replication

Infection by HIV can result in a state of -The provirus is integrated into the host genome but not expressed

True viral latency

Such cells persist in the face of an immune response because they produce no viral antigens and, since there is no viral replication, latent HIV is not sensitive to

Anti-viral agents

Latently-infected cells may later become activated and produce

Virus

HIV and other lentiviruses encode six small proteins not produced by other

Retroviruses

Bind to proteinubiquitin ligases, recruit specific host-cell proteins for ubiquitinylation, and promote their destruction by the proteosome

Vif, vpr, and vpu

What are the 6 regulatory proteins?

Tat, rev, nef, vif, vpu, and vpr

Powerful stimulator (100x) of transcription from the HIV promoter

Transactivator (tat)

Inhibits splicing of viral transcripts

Rev

Named for a putative ‘negative effect’ -Actually stimulates HIV replication and may be responsible for damage to the immune system

Nef

Persons infected with nef-defective HIV are ‘slow-progressors’ to

AIDs

Present in virion, required for infectivity

Virion Inefectivity Factor (vif)

Causes degradation of a DNA cytosine deaminase APOBEC which produces mutagenic damage to reverse transcripts

Vif

Stimulates virus release from the cell surface by delivering CD4 to the proteosome, and reducing cellsurface tetherin

Vpu

A protein that binds virions to the cell surface and promotes their endocytosis

Tetherin

Present in virion, may aid in transport of the viral core to nucleus; blocks cell division cycle in G2, when HIV transcription is more efficient than in G1

Vpr

Tat is an activator of

HIV transcription

Binds not to the HIV promoter but to tar (tat response element) of the transcript, which forms a stem-loop structure

Tat

Tar-bound tat binds cellular proteins which stimulate

Transcription

One is a protein kinase which phosphorylates the C-terminal domain of -Facilitates promoter clearance and rapid transcription

RNA polymerase

Rev prevents splicing of HIV mRNA by binding to

Rev Response Element (RRE) and exportins

Proteins which transport molecules out of the nucleus

Exportins

Early after infection, Rev levels are low and most viral transcripts are fully spliced, so that the small regulatory proteins are

Translated

As Rev accumulates, splicing is blocked, and unspliced and singly-spliced transcripts are able to leave the

Nucleus

Nef-defective Simian AIDS virus (SIV) failed to produce disease and in fact gave rise to a

Protective immune response

Expression of Nef in transgenic mice produces an

AIDS-like syndrome

This suggests that nef may play a key role in

AIDS pathology

Has an attached fatty acid and is bound to the plasma membrane, where it may alter intracellular signaling from membrane receptors and so alter transcription

Mature Nef

Down-regulates expression of CD4, MHC antigens, and cytokines, including IL-2 and IFN-γ

Nef

Induces macrophages to secrete soluble factors which up-regulate proteins on resting T cells, causing them to become susceptible to HIV infection

Nef

A cellular defense against retroviruses is

APOBEC

A deaminase that converts cytosine to uracil in viral DNA, creating mutations

APOBEC

The deaminase is incorporated into new virions and acts on the DNA strands produced by

Reverse transcription

Incorporated into HIV virions and excludes the deaminase APOBEC

Wif

One member of this protein family produces an intestine-specific form of Apo-B shorter than the liver form, by converting a cytosine in mRNA to uracil and creating a stop codon

Vif

Another member of the Vif family causes hypermutation of

Ig-gene

A host protein used by HIV to defend itself

Cyclophilin

Cyclophilin was named because it binds the immunosuppressant

Cyclosporin A

Mammalian cells contain ‘restriction factors’, proteins which bind CA proteins of infecting virions and block

Virus Replication

Binds Cyclophilin; it is incorporated into virions and, in an as-yet-unknown way, blocks a ‘restriction factor’

HIV CA

Typically follows exposure to HIV by 4-8 weeks. Symptoms are non-specific and may include (from most to least common) fever, lymphadenopathy, rash, pharyngitis, myalgia, diarrhea, headache, nausea, hepatosplenomegaly, peripheral- or CNS symptoms

Acute HIV infection

Acute HIV infection typically presents how long after initial infection?

4-8 Weeks

In acute disease there is rapid viral replication and high-level

Viremia

Can be found in the blood during acute HIV infection?

Infectious virus and CA (p24) antigen

After a few weeks, HIV-specific CTL appear and a strong cell-mediated immune response clears virus from the

Bloodstream

Anti-HIV antibodies (seroconversion) may not appear until

2-6 Months after infection

Gut lymphoid tissue is a major site of early

HIV replication

Massive early loss of T cells creates “holes” in the T-cell repertoire as clones of memory cells are eliminated by the

Virus

T cells with anti-HIV specificity may be especially susceptible to

Infection and killing

Binds integrin α4β7

HIV SU protein

The receptor which causes memory T cells to ‘home’ to mucosal lymphoid tissue

Integrin α4β7

This in turn up-regulates the membrane protein

LFA-1

Promotes cell-cell association of T cells and may promote cell-to-cell spread of HIV

LFA-1

Untreated, the median interval between seroconversion and development of AIDS is

10.5 years

This period is known as the

Asymptomatic period

Patients do not feel ill, and unless diagnosed, do not curtail activities that transmit the virus to others

Asymptomatic period

During the asymptomatic period, plasma viremia is typically low due to production of

Anti-HIV antibodies

During the asymptomatic period, dendritic cells trap these immune complexes and remove virus from the circulation; however this may facilitate infection of dendritic cells and/or transfer of virus to

T cells

Plasma virus load determines the speed of progression to

Symptomatic disease

Which cell type has the longest half-life when treated with HIV drugs?

Infected macrophages and dendritic cells

During the ‘asymptomatic period’ there is slow but steady alteration of the

Immune system

Early there is B-cell dysregulation, polyclonal B-cell proliferation, and proliferation of

CD8 T cells

Later, although the total concentration of circulating lymphocytes does not change, the ratio of CD4+ to CD8+ cells progressively

Declines

Within the TH population, we see an

Increase in TH2 cells and decrease in TH1 cells

T-cell proliferation and CMI are compromised and may ultimately lead to failure of the anti-HIV

CTL response

Response of T-cells to previously-encountered antigens also declines, perhaps because HIV preferentially infects

Memory T cells

Lymphadenopathy, fever, weight loss, persistent diarrhea, and Candida infection (the “AIDS-related” complex or ARC), are the initial manifestations of

Immune-system failure?

Defined by rapid decline of CD4+ lymphocytes, rapid increase in plasma viremia, and development of opportunistic infections -The last stage of HIV disease

AIDS